In this application Dr. Lindon J. Eaves is requesting five years of support to develop methods for analyzing genotype by environment interactions (GxE) in man. He will concentrate upon the interaction of environmental factors with major gene differences that affect dichotomous variables. Models of segregation analysis will be developed to allow for interaction of environmental risk factors with offspring and maternal genotypes for dichotomous traits. Existing computer programs will be modified to analyze data on extended twin kinships comprising twins, their parents, spouses and offspring. Simulation studies will explore the power of segregation analysis to detect effects of major genes on genotype by environment interaction for liability against backgrounds of other genetic, maternal and environmental effects. The methods tested on simulated data will then be applied to detect effects of GxE on liability to cardiovascular disease and birth defects in an existing data base on the extended kinships of approximately 6,000 male and female monozygotic and dizygotic twin pairs. The effects of fetal and maternal genotype on sensitivity to such environmental variables as alcohol, tobacco consumption, age and maternal age, and socio-economic status will be examined.